EP1043307B1 - 3-Amino-3-arylpropan-1-ol-Derivate, deren Herstellung und Verwendung - Google Patents

3-Amino-3-arylpropan-1-ol-Derivate, deren Herstellung und Verwendung Download PDF

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Publication number
EP1043307B1
EP1043307B1 EP00104477A EP00104477A EP1043307B1 EP 1043307 B1 EP1043307 B1 EP 1043307B1 EP 00104477 A EP00104477 A EP 00104477A EP 00104477 A EP00104477 A EP 00104477A EP 1043307 B1 EP1043307 B1 EP 1043307B1
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Prior art keywords
cyclohexanol
corresponding hydrochloride
dimethylaminophenylmethyl
hydrochloride
mmol
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English (en)
French (fr)
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EP1043307A3 (de
EP1043307A2 (de
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Bernd Dr. Sundermann
Babette-Yvonne Dr. Kögel
Hagen-Heinrich Dr. Hennies
Helmut Dr. Buschmann
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Gruenenthal GmbH
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Gruenenthal GmbH
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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Definitions

  • Classic opioids such as e.g. Morphine are in therapy strong to strong pain well effective. Your commitment however, due to the known side effects e.g. Respiratory depression, Vomiting, sedation, constipation, addiction, dependency and tolerance development limited. You can therefore only under special precautions, such as special prescriptions over a longer period Period or in higher dosages (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990). Besides, they are in some painful conditions, especially in neuropathic ones Pain, less effective.
  • the object underlying the invention was to a new structural class of analgesic substances to be found, which are suitable for pain therapy. Further Tasks were to find active ingredients that also for use as a local anesthetic and / or antiarrhythmic and / or antiemetic and / or nootropic (Neurotropic) and / or for the treatment / therapy of cardiovascular diseases and / or urinary incontinence and / or diarrhea and / or pruritus and / or alcohol and / or Drug and / or drug addiction and / or inflammations are suitable. As a rule, they are suitable Substances are also used to treat depression and / or to increase vigilance and / or increase libido.
  • the class of compounds of the general Formula I is characterized by a pronounced analgesic Effect distinguishes.
  • the compounds show the general formula I clear affinity to Binding site 2 of the sodium channel (BTX binding), to Benzothiazepine and the phenylalkylamine binding site of L-type calcium channels (diltiazem and verapamil binding) and inhibit synaptosomal norepinephrine reuptake (NA uptake inhibition).
  • connection class the general formula I also for use as a local anesthetic and / or antiarrhythmic and / or anti, emetic and / or nootropic (neurotropic) and / orzzy Treatment / therapy of cardiovascular diseases and / or urinary incontinence and / or diarrhea and / or Pruritus and / or alcohol and / or drug and / or Drug dependence and / or inflammation suitable.
  • the class of compounds is the general one Formula I also for vigilance increase and / or Libido enhancement and / or treatment of depression.
  • the invention therefore relates to substituted 3-amino-3-arylpropan-1-ols of general formula I, wherein the radicals R 1 to R 5 and A have the abovementioned meaning and the corresponding diastereomers or enantiomers in the form of their bases or salts of physiologically acceptable acids, wherein 1-benzyl-2- (dixnethylaininopheiiylthyl) -cyclohexanol, its diastereomers and its enantiomers are excluded in the form of their base and its reaction product with methyl iodide.
  • R 3 is a substituted C 1-3 alkyl-phenyl of the formula XII
  • R 4 to R 5 and A have the meaning according to the definition of the general formula I or Compounds of the general formula I in which R 1 and R 2 together form a (CH 2 ) 2-6 ring, in particular a (CH 2 ) 4 ring, which is optionally phenyl-substituted
  • R 3 is an aryl radical optionally having heteroatoms in the Ring system and the substituents R 6 to R 8 on the aryl ring
  • R 4 to R 5 and A have the meaning according to the definition of the general formula I or Compounds of the general formula I in which R 1 and R 2 together form a (CH 2 ) 4 ring which is optionally phenyl
  • Compounds of the invention are also compounds of general formula I as diastereomers or enantiomers in Form their bases or salts of physiological contractual acids.
  • the compounds of the invention including the excluded compounds as a mixture of enantiomers in not equimolar amounts as active ingredient in one Medicinal products, if appropriate in addition to other active substances, used.
  • the proportion of one Enantiomers between 5 and 45 mass percent.
  • C 1-6 -alkyl in the context of the present invention means straight-chain or branched hydrocarbons having 1 to 6 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl.
  • C 3-7 -cycloalkyl in the context of the present invention means saturated cyclic hydrocarbons or straight-chain or branched alkyl radicals containing saturated cyclic hydrocarbons having a total of 3 to 7 carbon atoms. Examples include cyclopropyl, cyclopropylmethyl, methylcyclopropyl, cyclobutyl, 1-Cyclopropyiethyl, 2-cyclopropylethyl, cyclopentyl, CyclopentyliriethyJ, cyclohexyl or cycloheptyl mentioned.
  • aryl means in the context of the present invention optionally mono- or polysubstituted, preferably aromatic ring systems which may optionally have heteroatoms in the ring system.
  • the aryl radicals are mono- or polysubstituted by the radicals R 9 to R 13 .
  • the preferably 5- or 6-membered unsaturated, optionally condensed with further rings, optionally mono- or polysubstituted heterocyclic compounds may have one or two heteroatoms, such as nitrogen, oxygen and / or sulfur in the ring system.
  • Exemplary are from the group of heteroaryls furan, Thiophene, pyrrole, pyridine, pyrimidine, quinoline, isoquinoline, Phthalazine or quinazoline listed.
  • the reaction of a Mannich base of the formula II with a Grignard compound R 3 Y, in which Y is MgCl, MgBr or MgI, or with an organolithium compound R 3 Li can be carried out in an aliphatic ether, for example diethyl ether and / or tetrahydrofuran, a hydrocarbon, for example hexane or toluene, or mixtures of hydrocarbons and aliphatic ethers, at temperatures between -70 ° C and + 110 ° C.
  • the preparation of a Grignard compound R 3 Y can be carried out with or without the addition of a Mit Technologyreagenzes, preferably 1,2-dibromoethane.
  • aromatic Grignard compounds R 3 Y can be obtained by reacting an aromatic iodide R 3 I with an organomagnesium compound, for example, isopropylmagnesium chloride or diisopropylmagnesium, by iodine-magnesium exchange.
  • Organolithium compounds R 3 Li can be prepared from OrganohalogenENSenR 3 Z, where obtained Z is Cl, Br or I, by reaction with, for example, an n-butyllithium / hexane solution by halogen-lithium exchange.
  • the Mannich bases of the formula II can be obtained by reacting enamines of the formula III with a imminium salt of the formula IV in which Y is, for example, Cl - , AlCl 4 - , Br - or I - .
  • the enamines are prepared by methods known in the literature from ketones of the formula V and secondary amines, for example dimethylamine, pyrrolidine, piperidine or morpholine (Acta Chem. Scand. B 38 (1984) 49-53).
  • the imminium salts are prepared by methods known from the literature by reacting aminals of the formula VI with acid chlorides, for example acetyl chloride or thionyl chloride (Houben-Wey] methods of Organic Chemistry, E21b (1995) 1925-1929).
  • the imminium salts of formula IV need not be isolated but can be generated in situ and with Enamines of formula III converted to Mannich bases of formula II (Angew Chem 106 (1994) 2531-2533). by virtue of the keto-enol tautomerism analogous enamine-lmin tautornery are instead of the enamines of formula III too Imine of formula VII can be used. Alternatively, ketones of the formula V also directly with imminium salts of the formula IV be implemented.
  • Mannich bases of the formula II can also be prepared by reacting enamines of the formula III with an aromatic aldehyde of the formula VIII and a secondary amine HNR 4 R 5 , also in the form of the corresponding hydrochloride HNR 4 R 5 , HCl, in the presence of triethylamine, chlorotrimethylsilane and Sodium iodide can be prepared directly (Synlett (1997) 974-976).
  • the Mannich bases of formula II are obtained by the methods described above, depending on the reaction conditions, preferably with the relative configuration of formula IIa in which the amino group is anti to R 1 .
  • the compounds of the formula IIa can be obtained diastereomerically by crystallization, and also of their salts, for example the hydrochlorides, or by chromatographic separation.
  • 3-Amino-3-arylpropan-1-ol compounds of the general formula I in which R 3 contains a phenolic substituent can be, for example, from the corresponding methyl ether derivatives with diisobutylaluminum hydride in an aromatic hydrocarbon, for example toluene, at a temperature between 60 ° C and 130 ° C produce (Synthesis (1975) 617-630).
  • the compounds of formula I can be physiologically compatible acids, for example hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, Formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, Mandelic acid, fumaric acid, lactic acid, citric acid, Glutamic acid and / or aspartic acid, in a known manner into their salts.
  • the salt formation in a solvent for example diethyl ether, Diisopropyl ether, alkyl acetate, acetone and / or 2-butanone carried out.
  • a solvent for example diethyl ether, Diisopropyl ether, alkyl acetate, acetone and / or 2-butanone carried out.
  • hydrochlorides is also suitable trimethylchlorosilane in aqueous Solution.
  • the substances corresponding to formula I are toxicological harmless, so that they are as pharmaceutical Active substance in medicaments are suitable.
  • Another item The invention therefore relates to medicaments containing Active ingredient at least one compound of the general Formula I.
  • the inventive Medicines as analgesics.
  • the invention Substances are therefore suitable in addition to the particular preferred use in pain therapy too Use as local anastele and / or antiarrhythmic and / or antiemetic and / or nootropic (neurotropic) and / or for the treatment / therapy of cardiovascular Diseases and / or urinary incontinence and / or diarrhea and / or pruritus and / or alcohol and / or drugs and / or Drug dependence and / or inflammation.
  • the compounds are the general Formula I is also used to treat depression and / or to increase vigilance and / or increase libido.
  • the analgesics according to the invention contain, in addition to at least a 3-amino-3-arylpropan-1-ol derivative of the formula I support materials, fillers, solvents, diluents, Dyes and / or binders.
  • the selection the auxiliaries and the amounts to be used depends on whether the drug is taken orally, intravenously, intraperitoneal, intradermal, intramuscular, intranasal, buccal or local, for example, to infections on the skin, mucous membranes and on the eyes shall be.
  • Preparations are suitable for oral administration in the form of tablets, dragees, capsules, Granules, drops, juices and syrups, for the parenteral, topical and inhalative application solutions, Suspensions, easily reconstitutable dry preparations as well as sprays.
  • Compounds of the invention Formula I in a depot, in dissolved form or in one Patch, optionally with the addition of skin penetration Promoters, are suitable percutaneous application preparations. Orally or percutaneously applicable preparations
  • the compounds of the invention can be Release Formula 1 with a delay.
  • the amount of drug to be administered to the patient varies depending on the weight of the patient, from the type of application, the indication and the severity the disease. Usually, 0.5 to 500 mg / kg at least one 3-amino-3-arylpropan-1-ol derivative of Formula 1 applied.
  • the assay for analgesic activity was carried out in phenyl-quinone-induced writhing in the mouse (modified according to IC Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240).
  • male NMRI mice weighing 25 to 30 g were used.
  • Ten minutes after the intravenous administration of the test substances groups of 10 animals per substance dose received 0.3 ml / mouse of a 0.02% strength aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen, preparation of the solution with the addition of 5% ethanol and storage in a water bath at 45 ° C) intraperitoneally.
  • the ED 50 values with 95% confidence range of the writhing reaction were calculated from the dose-dependent decrease of the writhing reactions in comparison to parallel examined phenylquinone control groups by regression analysis (evaluation program Martens EDV Service, Eckental).
  • the biological membrane material was isolated from rat cerebrocortex.
  • the ligand used was [ 3 H] -cis - (+) - diltiazem (5 nM in the reaction mixture). Incubate for 20 minutes at 25 ° C. Non-specific binding is defined as the radioactivity which is measured in the presence of ( ⁇ ) -diltiazem (10 -6 M in the reaction mixture).
  • the unbound portion of the radioactive ligand is separated after completion of the incubation by means of a filtration process on Whatman Glasfiber GF / B membranes. The membranes are then measured after a washing process on the ⁇ -counter.
  • the method has been prepared following the publication of Schoemaker and Langer (H.
  • Phenylalkylamine binding site (verapamil binding)
  • the biological material (ion channel particle) has been prepared following the publication of Reynolds, Gould and Snyder (IJ Reynolds, RJ Gould and SH Snyder (1983) J. Pharmacol., 95 , 319-321).
  • the radioligand used was N-methyl- [ 3 H] -verapamil (2 nM in the reaction).
  • Non-specific binding is defined as that radioactivity which is determined in the presence of non-radioactive verapamil (10 -4 M in the mixture). Incubate at 25 ° C for 45 minutes. Subsequent filtration via Whatman GF / B filter with attached wash. Determination of the radioactivity remaining on the filter (ion channel binding) at the ⁇ -counter.
  • the binding site 2 of the sodium channel is the so-called batrachotoxin (BTX) binding site.
  • the ligand used was [ 3 H] -batrachotoxin A20 ⁇ -benzoate (10 nM in the reaction mixture).
  • These ion channel particles were enriched from the rat Cerebrocortex according to Gray and Whittaker (EG Gray and VP Whittaker (1962) J. Anat. 76 , 79-88).
  • Non-specific binding is defined as the radioactivity measured in the presence of veratridine (0.3 mM in the reaction). Incubation at. 37 ° C for 120 min.
  • the assay conditions have been performed following the publication of Pauwels, Leysen and Laduron (PJ Pauwels, JE Leysen and PM Laduron (1986) Eur. J. Pharmacol., 124 , 291-298).
  • IC 50 values are obtained, which can be converted into inhibitor constants (K i ) according to the "Cheng-Prusoff equation" (YC Cheng and WH Prusoff (1973) Biochem. Pharmacol., 22 , 3099-3108).
  • K i inhibitor constants
  • the IC 50 values were obtained using the computer program " Figure P” (Version 6.0, Biosoft, Cambridge, England). Km values were calculated according to Lineweaver and Burk (H. Lineweaver and D. Burk (1934) J. Am. Chem. Soc 56 , 658-666). To represent K D values, the computer program "Ligand” (Version 4, Biosoft, England) has been used.
  • ether means diethyl ether.
  • racemate separations were performed on a Chiracel OD column 250 x 4.6 mm with precolumn made by Daicel.
  • RT means room temperature, vol.% By volume, m 2 mass% and% ee enantiomeric excess in percent.
  • the mother liquor of the filtered-off base / tartaric acid mixture was concentrated and, as in the previously obtained precipitate, the base was liberated with sodium hydroxide solution and then a hydrochloride was precipitated with chlorotrimethylsilane / water in 2-butanone. From this, in turn, the base was liberated with sodium hydroxide solution and 0.62 g (1.6 mmol) of crude base was obtained.
  • Example 1 From both bases was after Example 1 (3rd step) with chlorotrimethylsilane / water in 2-butanone Hydrochloride pleased.

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EP00104477A 1999-04-07 2000-03-08 3-Amino-3-arylpropan-1-ol-Derivate, deren Herstellung und Verwendung Expired - Lifetime EP1043307B1 (de)

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DE4426245A1 (de) 1994-07-23 1996-02-22 Gruenenthal Gmbh 1-Phenyl-3-dimethylamino-propanverbindungen mit pharmakologischer Wirkung
DE19915602A1 (de) * 1999-04-07 2000-10-19 Gruenenthal Gmbh 3-Amino-4-arylpropan-1-ol-Derivate, deren Herstellung und Verwendung
DE19963175A1 (de) * 1999-12-27 2001-07-12 Gruenenthal Gmbh Verwendung von substituierten 4-Amino-1-phenylbutan-2-ol-Verbindungen als Arzneimittel
DE10025238A1 (de) * 2000-05-22 2001-11-29 Gruenenthal Gmbh Verwendung substituierter 1-Amino-5-phenylpentan-3-ol- und/oder 1-Amino-6-phenylhexan-3-ol- Verbindungen als Arzneimittel
DE10049483A1 (de) * 2000-09-29 2002-05-02 Gruenenthal Gmbh Substituierte 1-Aminobutan-3-ol-Derivate
DE10049481A1 (de) * 2000-09-29 2002-05-02 Gruenenthal Gmbh Substituierte C-Cyclohexylmethylamin-Derivate
DE10108307A1 (de) 2001-02-21 2002-08-29 Gruenenthal Gmbh Substituierte Propan-1,3-diamin-Derivate
DE10132747A1 (de) * 2001-07-05 2003-01-23 Gruenenthal Gmbh Substituierte 1-Aryl-but-3-enylamin- und 1-Aryl-but-2-enylaminverbindungen
DE10161809A1 (de) * 2001-12-14 2003-06-26 Gruenenthal Gmbh Arzneimittel enthaltend N,N'-disubstituierte Piperazin-Verbindungen
DE10161644A1 (de) * 2001-12-14 2003-06-26 Gruenenthal Gmbh N,N'-disubstituierte Piperazin-Verbindungen
DE10161818A1 (de) * 2001-12-14 2003-06-26 Gruenenthal Gmbh Substituierte 1,5-Diaminopentan-3-ol-Verbindungen
DE10164581A1 (de) * 2001-12-14 2003-06-26 Gruenenthal Gmbh Substituierte Aminoalkohole
DE10213051B4 (de) * 2002-03-23 2013-03-07 Grünenthal GmbH Substituierte 4-Aminocyclohexanole
DE102004034619A1 (de) * 2004-07-16 2006-02-23 Grünenthal GmbH Substituierte Aminoverbindungen als 5-HT/NA Uptakehemmer
DE102005061428A1 (de) * 2005-12-22 2007-08-16 Grünenthal GmbH Substituierte Cyclohexylmethyl-Derivate
RU2470011C2 (ru) * 2007-05-31 2012-12-20 Сепракор Инк. Циклоалкиламины, содержащие в качестве заместителя фенил, как ингибиторы обратного захвата моноаминов
AU2015202379B2 (en) * 2007-05-31 2016-10-13 Sunovion Pharmaceuticals Inc. Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors
CN118108610A (zh) * 2024-04-30 2024-05-31 山东新华制药股份有限公司 盐酸去甲曲马多的制备方法

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AT28628B (de) * 1905-11-04 1907-06-10 Neue Photographische Ges Ag Verwandlungsbilder, bei welchen die Umwandlung des Bildes durch Lichtwirkung hervorgerufen wird.
GB657301A (en) * 1948-02-25 1951-09-19 Wellcome Found Improvements in and relating to the preparation of substituted amino-alcohols and derivatives thereof
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